Processes for preparing 3-Arylsulfur hydroxamic acids

ABSTRACT

This invention provides processes for the preparation of a compound of Formula I:wherein:Y is hydroxy or XONX, where each X is independently hydrogen, lower alkyl or lower acyl;R1 is hydrogen or lower alkyl;R2 is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, or R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclo group;R3 is aryl; andn is 0, 1 or 2.The invention also provides novel aryl haloalkyl sulfide intermediates useful for the preparation of compounds of Formula I and novel methods of preparing aryl alkyl sulfides.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. 119(e) of U.S.Provisional Application Ser. No. 60/089,778, filed Jun. 18, 1998, herebyincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to methods of preparing matrix metalloproteaseinhibitors, particularly 3-arylsulfur hydroxamic acids.

2. Background Information

I. MMP Inhibitors

Matrix metalloproteases (“MMPs”) are a family of proteases (enzymes)involved in the degradation and remodeling of connective tissues. MMPexpression is stimulated by growth factors and cytokines in the localtissue environment, where these enzymes act to specifically degradeprotein components of the extracellular matrix, such as collagen,proteoglycans (protein core), fibronectin and laminin. Excessivedegradation of extracellular matrix by MMPs is implicated in thepathogenesis of many diseases, including rheumatoid arthritis,osteoarthritis, multiple sclerosis, bone resorptive diseases (such asosteoporosis), chronic obstructive pulmonary disease, cerebralhemorrhaging associated with stroke, periodontal disease, aberrantangiogenesis, tumor invasion and metastasis, corneal and gastriculceration, ulceration of skin, aneurysmal disease, and in complicationsof diabetes.

Furthermore, inhibitors of MMP also are known to substantially inhibitthe release of tumor necrosis factor (TNF) from cells and therefore maybe used in the treatment of conditions mediated by TNF. Such usesinclude, but are not limited to, the treatment of inflammation, fever,cardiovascular effects, hemorrhage, coagulation and acute phaseresponse, cachexia and anorexia, acute infections, shock states,restenosis, graft versus host reactions and autoimmune disease.

MMP inhibition is, therefore, recognized as a good target fortherapeutic intervention. Consequently, inhibitors of MMPs provideuseful treatments for diseases associated with the excessive degradationof extracellular matrix and diseases mediated via TNF and several MMPinhibitors are currently being developed for such uses.

One particular class of MMP inhibitors are the 3-arylsulfur hydroxamnicacids described in EP 0 780 386 A1, published Jun. 25, 1997. Thispublication discloses MMP inhibitors of Formula I,

Y—C(═O)—C(R¹)(R²)—CH₂—S(O)_(n)R³

where n, Y, R¹, R² and R³ are as described below in the Summary of theInvention.

WO 97/24117, published Jul. 10, 1997, discloses 3-aryl sulfur hydroxamicacids of formula,HON(H)—C(═O)—C_(p)(R₁)(R₂)—C(R₃)(R₄)—S(O)_(n)—C_(m)(R₅)(R₆)—Ar, where p,m, n and R₁, R₂, R₃, R₄, R₅, R₆ and Ar are as described in WO 97/24117.

WO 98/05635, published Feb. 12, 1998, discloses 3-arylsulfur hydroxamicacids of formula B—S(O)₀₋₂—CHR¹—CH₂—CO—NHOH, where B and R¹ are asdescribed in in WO 98/05635.

WO 98/13340, published Apr. 2, 1998, discloses β-sulfonyl hydroxamicacids of HONHC(═O)—CHR₂—CH2—S(O)₂R₁ where R₁ and R₂ are as describedtherein.

However, the processes disclosed in these publications for preparing3-arylsulfur hydroxamic acids proceed via the nucleophilic attack of athiol on the β-carbon of a carboxylate derivative, either displacing aleaving group at the β-carbon or performing a Michael reaction on an α,βunsaturated ester or acid. Thus, the disclosed processes are limited bythe availability of the corresponding thiols and the β-substitutedcarboxylate derivatives and α,β unsaturated esters. This inventionprovides novel processes and novel intermediates that are not dependenton the availability of the reagents used in the above publications.

The use of 3-arylsulfonyl hydroxamic acids as MMP inhibitors is alsodescribed in WO 97/49679 A1, published Dec. 31, 1997.

II. Preparation of Aryl Alkyl Sulfides

Aryl haloalkyl sulfides are valuable intermediates in synthetic organicprocesses and they are commonly made by free radical halogenation of aprecursor aryl alkyl sulfide. The aryl alkyl sulfide is in turntypically available via sulfonation of a precursor aryl hydrocarbon,reduction to an aryl thiol and alkylation of the thiol. It would beuseful to have methods of directly converting arylsulfonyl derivativesto aryl methyl sulfides.

There have been various reports of the reactions between trialkylphosphites and aryl sulfonyl derivatives. See, for example, R. W.Hoffman, T. R. Moore and B. J. Kagan, (“The Reaction between TriethylPhosphite and and Alkyl and Aryl Sulfonyl Chlorides”) J. Am. Chem. Soc.,78:6413-6414 (1956); J. M. Klunder and K. Barry Sharpless, (“AConvenient Synthesis of Sulfinate Esters from Sulfonyl Chlorides”) J.Org. Chem., 52:2598-2602 (1987); and J. Cadogan (“Oxidation of TervalentOrganic Compounds of Phosphorous”) Quarterly Reviews, 16:208-239 (1962).The reaction of benzensulfenyl chloride with triethylphosphite to yieldethyl phenyl sulfide has also been reported, T. Mukaiyama and H. Ueki,(“The Reactions of Sulfur-containing Phosphonium Salts”) Tetr. Lett.,35:5429-5431 (1967). Aryl sulfonyl chlorides have also been converted toaryl methyl sulfides in three steps by treatment of an aryl sulfonylchloride with lithium diphenylphosphide, Ph₂PLi, to afford aP-diphenyl-aryl sulfophosphamide followed by cathodic reduction andmethylation of the resulting aryl thiolate, J. Pilard and J. Simonet.(“The Cathodic Cleavage of the S—P Bond. Synthesis and ElectrochemicalBehaviour of Sulfonamide Phosphorous Analogues”), Tetr. Lett.,38(21):3735-3738 (1997).

SUMMARY OF THE INVENTION

In one aspect, this invention provides processes for the preparation ofa compound of Formula I:

Y—C(═O)—C(R¹)(R²)—CH₂—S(O)_(n)R³  Formula I

wherein:

Y is hydroxy or XONX—, where each X is independently hydrogen, loweralkyl or lower acyl;

R¹ is hydrogen or lower alkyl;

R² is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,or R¹ and R² together with the carbon atom to which they are attachedform a cycloalkyl or heterocyclo group;

R³ is aryl; and

n is 0, 1 or 2;

comprising the steps of:

(1) alkylating a compound of Formula II,

RO—C(═O)—CH(R¹)(R²)  Formula II

where R is alkyl or hydrogen, with an arylmethylthio derivative ofFormula III, ArSCH₂—Z, wherein Ar is an aryl group and Z is a leavinggroup, to provide a compound of Formula IV,

RO—C(═O)—C(R¹)(R²)—CH₂SAr,  Formula IV

 and

(2) converting the compound of Formula IV to a compound of Formula I byreplacing the group RO— with XONH— and optionally oxidizing the ArSgroup as necessary in either order.

The invention also provides novel aryl haloalkyl sulfide and aryl alkylsulfide intermediates useful for the preparation of compounds of FormulaI and novel methods of preparing aryl alkyl sulfides.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the term “(C_(p-q))alkyl” means a linear or branchedfully-saturated hydrocarbon radical having p to q carbon atoms; forexample, a “C₁₋₄ alkyl” means a linear or branched fully saturatedhydrocarbon radical having one to four carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, or tert-butyl.

Unless otherwise specified, the term “lower alkyl” means a C₁₋₄ alkylradical.

As used herein, the term “(C₃₋₆)cycloalkyl” means a fully saturatedcyclic hydrocarbon radical of three to six ring carbon atoms, e.g.,cyclopropyl, cyclopentyl and the like.

As used herein, the term “lower acyl” refers to a group —C(═O)R, where Ris a (C₁₋₄)alkyl radical.

As used herein, the term “loweralkoxy” refers to a group —OR, where R isa (C₁₋₄)alkyl radical.

As used herein, the term “(C₇₋₁₀)alkoxy” refers to a group OR, where Ris a (C₇₋₁₀)alkyl radical.

As used herein, the term “aryl” means a monovalent monocyclic orbicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, andoptionally substituted independently with one, two or three substituentsselected from alkyl, haloalkyl, cycloalkyl, halo, nitro, cyano,optionally substituted phenyl, —OR (where R is hydrogen, alkyl,haloalkyl, cycloalkyl, optionally substituted phenyl), acyl, —COOR(where R is hydrogen or alkyl). More specifically the term arylincludes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, andderivatives thereof.

As used herein, the term “arylene” means a divalent monocyclic orbicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, andoptionally substituted independently with one, two or three substituentsselected from alkyl, haloalkyl, cycloalkyl, halo, nitro, cyano,optionally substituted phenyl, —OR (where R is hydrogen, alkyl,haloalkyl, cycloalkyl, optionally substituted phenyl), acyl, —COOR(where R is hydrogen or alkyl). More specifically the term arylincludes, but is not limited to, 1,4-phenylene and 1,2 phenylene.

“Optionally substituted phenyl” means a phenyl group which is optionallysubstituted independently with one, two or three substituents selectedfrom alkyl, haloalkyl, halo, nitro, cyano, —OR (where R is hydrogen oralkyl), —NRR′ (where R and R′ are independently of each other hydrogenor alkyl), —COOR (where R is hydrogen or alkyl) or —CONR′R″ (where R′and R″ are independently selected from hydrogen or alkyl).

“Heterocyclo” means a saturated monovalent cyclic group of 3 to 8 ringatoms in which one or two ring atoms are heteroatoms selected from N, O,or S(O)_(n), where n is an integer from 0 to 2, the remaining ring atomsbeing C. The heterocyclo ring may be optionally fused to a benzene ringor it may be optionally substituted independently with one or moresubstituents, preferably one or two substituents, selected from alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, halo, cyano,acyl, monosubstituted amino, disubstituted amino, carboxy, oralkoxycarbonyl. More specifically the term heterocyclo includes, but isnot limited to, pyrrolidino, piperidino, morpholino, piperazino,tetrahydropyranyl, and thiomorpholino, and the derivatives thereof.

“Leaving group” has the meaning conventionally associated with it insynthetic organic chemistry i.e., an atom or group capable of beingdisplaced by a nucleophile and includes halogen, alkanesulfonyloxy,arenesulfonyloxy, amino, alkylcarbonyloxy, arylcarbonyloxy, such aschloro, bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy,N,O-dimethylhydroxylamino, acetoxy, and the like.

In one aspect, this invention provides a process for the preparation ofa compound of Formula I:

Y—C(═O)—C(R¹)(R²)—CH₂—S(O)_(n)R³  Formula I

wherein:

Y is hydroxy or XONX, where each X is independently hydrogen, loweralkyl or lower acyl;

R¹ is hydrogen or lower alkyl;

R² is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,or R¹ and R² together with the carbon atom to which they are attachedform a cycloalkyl or heterocyclo group;

R³ is aryl; and

n is 0, 1 or 2;

comprising the steps of:

(1) alkylating a compound of Formula II,

RO—C(═O)—CH(R¹)(R²)  Formula II

where R is alkyl or hydrogen, with an arylmethylthio derivative ofFormula III, ArSCH₂—Z, wherein Ar is an aryl group and Z is a leavinggroup, to provide a compound of Formula IV,

RO—C(═O)—C(R¹)(R²)—CH₂SAr  Formula IV

 and

(2) converting the compound of Formula IV to a compound of Formula I byreplacing the group RO— with XONH— and optionally oxidizing the ArSgroup as necessary in either order.

Unlike the methods disclosed in EP 0 780 386 A1, published Jun. 25,1997, WO 97/24117, published Jul. 10, 1997, WO 98/05635, published Feb.12, 1998 and WO 98/13340, published Apr. 2, 1998, for the synthesis of3-arylsulfur hydroxarnic acids, the processes of the present inventionproceed via the alkylation of the α-carbon of a carbonyl group with ahalomethyl aryl sulfide. The invention also provides novel halomethylaryl sulfides, such as chlorophenoxyphenyl chloromethyl sulfide andmethods for their preparation. Thereby, the inventors are able toprepare compounds of Formula I by novel processes not previouslyavailable.

These reaction processes are shown in Scheme A, below.

Compounds of Formula IV may be converted to compounds of Formula I byconversion of the carboxyl group to a group —C(═O)—L where L is aleaving group under nucleophilic displacement conditions followed bydisplacement of L with hydroxylamine (or an alkylated derivative). Theresulting hydroxamic acid is then oxidized as necessary to give thedesired sulfoxide or sulfone. Oxidation to the sulfoxide is accomplishedby treatment with mild oxidizing agents such as sodium or potassiummetaperiodate or one equivalent potassium peroxymonosulfate (Oxone™).Other oxidants that may be used include peracids, (e.g. performic orperacetic acid) or sodium perborate/organic acid mixtures (e.g.performic or peracetic acid). The reaction may be halted at thesulfoxide stage by limiting the quantity of reagents, temperature andreaction time. Further oxidation to the sulfone is accomplished bytreatment under more vigorous conditions with organic peracids such asm-chloroperbenzoic acid or two equivalents of sodium peroxymonosulfate.Alternatively, other oxidizing agents such as perborates, e.g., sodiumperborate, in a carboxylic acid solvent such as formic, acetic orpropionic acid may be used. These last two steps may also be reversed,i.e., oxidation of the sulfur moiety may precede conversion of the acidto the hydroxamate. However, overall yields are usually higher with theformer sequence.

Compounds of Formula II, RO—C(═O)—CH(R¹)(R²), can be purchased fromcommercial suppliers or are readily available by published proceduresknown to one of skill in the art. See, for example, EP 0 780 386 A1.

Compounds of Formula III, ArSCH₂—Z, are made by oxidation of theprecursor arylmethylthioether. Compounds ArSCH₂Cl are made by oxidationwith sulfuryl chloride in aprotic solvents such as methylene chloride,t-butylmethyl ether or hexane. The oxidation may be done at roomtemperature or at lower temperatures, e.g., from about 0-10° C. Otherreagents, such as N-chlorosuccinimide, may also be used. CompoundsArSCH₂Br are made by oxidation with sulfuryl bromide or other reagentssuch as N-bromosuccinimide.

Compounds of Formula III, ArSCH₂—Z, where Z is chloro or bromo may alsobe made from the corresponding thiol as shown below:

Arylmethylthioethers are generally available either from commercialvendors or published literature procedures. For example, they may bemade by sulfonylating an aryl compound to the corresponding sulfonicacid, reducing the sulfonic acid to a thiol and methylating the thiol.

Alternatively, as shown in Scheme B, the inventors have unexpectedlydiscovered that arylsulfonyl halides can be converted directly toarylmethylthioethers in one step by treatment with trimethylphosphite.The conversion proceeds best if the trimethylphosphite treatment isfollowed by treatment with a base. Either an organic base such as analkylamine (e.g. triethylamine) or a hydroxylic base such as an alkalimetal hydroxide or an alkaline earth metal hydroxide may be used.However, the conversion may also be accomplished, albeit in somewhatlower yield, without the addition of a base. In such processes, theyield of the aryl methyl sulfide may be increased by heating to elevatedtemperatures, e.g., as high as about 100° C., preferably as high asabout 130° C. (internal temperature). Consequently, the invention alsoprovides a novel method of preparing aryl methyl sulfides by directlyreducing/alkylating an arylsulfonyl halide with trimethyl phosphite.

The method is particularly useful for forming compounds of formulaArSCH₃, wherein Ar has the formula —Ar¹—A—Ar², where Ar¹ and Ar² arephenyl rings, each independently optionally substituted and A is a bond,CH₂ or —O—, and more particularly where, A is oxygen, Ar¹ is phenyl andAr² is 4-chlorophenyl.

Subsequent halogenation of ArSCH₃ then provides key intermediates offormula ArSCH₂—X where X is halo. Useful key intermediates include thosewhere Ar is —Ar¹—A—Ar², wherein Ar¹ and Ar² are independently optionallysubstituted phenyl, X is halo, A is oxygen, or CH₂. A particularlyuseful intermediate is that wherein Ar¹ is phenyl, Ar² is haloplhenyl,and A is oxygen.

Alkylation of a compound of Formula II with a compound of Formula IIImay be accomplished by conditions known to one of skill in the art suchas converting a compound of Formula II to an enolate or enol followed byreaction with a compound of Formula III. Other conditions includeforming the dianion of the acid (i.e., compound of Formula II where R═H)by treatment with two equivalents of a base such as lithiumdiusopropylamide or lithium hexamethyldisilazide and alkylating with oneequivalent of a compound of Formula III.

In one embodiment, a compound of Formula II was converted to asilylketene acetal as shown in Reaction Scheme C (where Silyl representsa silyl group), followed by Mukaiyama coupling of the acetal with acompound of Formula III. The coupling is generally done in an anhydrousaprotic solvent such as a halocarbon or hydrocarbon (methylene chloride,chloroform, benzene, toluene etc.) in the presence of a Lewis acid suchas zinc chloride, zinc bromide, zinc iodide, ferric bromide or titaniumtetrachloride. Silylketene acetals may be readily prepared fromcompounds of Formula II by procedures such as those described in C.Ainsworth, F. Chen, Y. N. Kuo “Ketene Alkyltrialkylsilyl Acetals:Synthesis, Pyrolysis and NMR Studies”) J. Organometallic Chem., 46:59-87(1972). A variety of silyl protecting groups, e.g.,t-butyldimethylsilyl, trimethylsilyl, etc. may be used. Silylketeneacetals can be formed from either the ester (R=alkyl) or acids (R═H) ofFormula II. Formation of the silylketene acetal from the acid may beaccomplished using two equivalents of base and quenching with twoequivalents of the silylating reagent. Subsequent alkylation with acompound of Formula III followed by a hydrolytic work up then directlyyields a carboxylic acid of Formula IV. Reagents that may be used toform the silylketene acetal include trimethylysilyl triflate,trimethylsilyl chloride or bromide, tert-butyldimethylsilyl chloride andbis-trimethylsilyl acetamide.

Alternatively, an enolate of a compound of Formula II may be directlyalkylated with a compound of Formula III, thus avoiding the intermediacyof the silylketene acetal. The enolate is formed under standardconditions, by treatment with a non-nucleophilic organic base such aslithium diisopropylamide or lithium hexamethyldisilazide, or a metalhydride such potassium hydride, under anhydrous conditions, typically atroom temperature, in a polar aprotic solvent such as tetrahydrofuran,dimethoxyethane or glyme and the like. Subsequent addition of a compoundof a Formula III followed by heating if necessary to refluxtemperatures, e.g., 60-80° C., provides an alkylated product of FormulaIV. The enolate may also be formed from the corresponding α-bromoesterof a compound of Formula II by treatment with zinc to form the zincenolate which can then be alkylated.

Though the processes described herein may be used to prepare a varietyof 3-arylsulfur hydroxamic acids and their corresponding carboxy andester derivatives, they are particularly useful for preparing compoundsof Formula I wherein the aryl group Ar is of the formula —Ar¹—A—Ar²,wherein Ar¹ and Ar² are phenyl rings, each independently optionallysubstituted and A is a bond, —CH₂— or —O—.

Other useful compounds that may be made by the methods of the inventioninclude compounds of Formula I where R¹ and R² together with the carbonatom to which they are attached form a cycloalkyl or heterocyclo group,particularly a tetrahydropyranyl group.

Additional useful hydroxamic acids that may be prepared include thosethat are α,α-disubstituted, i.e., neither R¹ nor R² are hydrogen.

Utility and Administration

As described earlier, the compounds made by these processes are MMPinhibitors, useful in treating a variety of diseases as disclosed in EP0 780 386 A1, published Jun. 25, 1997; WO 97/24117, published Jul. 10,1997; and WO 98/05635, published Feb. 12, 1998.

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Abbreviations used in the examples are defined as follows: “DMF” fordimethylformamide, “NaOH” for sodium hydroxide, “DMSO” fordimethylsulfoxide, “PTLC” for preparatory thin layer chromatography,“EtOAc” for ethyl acetate, “LDA” for lithium diisopropylamide and“TMSCl” for trimethylsilylchloride.

EXAMPLE Synthesis of4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-4-(N-hydroxycarboxamido)tetrahydropyran.

Scheme D shows a representative method of this invention for thepreparation of 14,4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-4-(N-hydroxycarboxamido)tetrahydropyran,a compound of Formula I, wherein:

Y is NHOH;

R¹ and R² together with the carbon atom to which they are attachedrepresent a tetrahydropyran-4-yl group; and

R³ is 4-chlorophenoxyphenyl.

Although Scheme D is directed towards the synthesis of a specific3-arylsulfur hydroxamic acid, it is to be understood that a similar setof reactions can be used to prepare other arylsulfur hydroxamic acids,carboxylic acids and esters by substituting appropriate startingmaterials and reagents as outlined in Reaction Schemes A-C.

A. Preparation of 4-(4-Chlorophenoxy)phenyl Chloromethyl sulfide

Step 1

Diphenylether 1, is available from Aldrich (Milawaukee, Wis.) and can beconverted to 4-(4′-chlorophenoxy)phenyl sulfonylchloride, compound 3,using known procedures, such as described in WO 97/20824.

Step 2

4-(4′-Chlorophenoxy)phenyl sulfonyl chloride (3.0 kg), 3, was dissolvedin three liters of toluene and the solution was added dropwise, withstirring, to 3.6 kg of trimethyl phosphite which had been preheated to60° C. The reaction was exothermic and the reaction was allowed to heatto 80°-90° C. during the addition. Thin layer chromatography indicated amixture of the desired thioether and two baseline products. The mixturewas refluxed until the pot temperature rose to ˜130° C. The mixture wascooled to ˜60° C. and 1 liter of methanol was added. Potassium hydroxidesolution (4.5 kg of 45% aqueous solution) was added dropwise, slowly,with rapid stirring to the reaction mixture. The addition was veryexothermic and the pot temperature was controlled to 65°-80° C. Themixture was then refluxed for 2 hrs. More toluene (6 liters) was addedand the mixture cooled to ˜60° C. The lower aqueous layer was separatedand the organic layer washed with 3 liters of water. The organic layerwas stripped to a low volume and 9 liters of isopropanol charged to thehot mixture. The solution was distilled until ˜3.5 liters of distillatehad been collected. The mixture was held at 45° C. for several hours andwas then cooled to ˜−10° C. and stirred several hours. The white,crystalline product was collected, washed with cold isopropanol anddried to yield 1.9 kg of 4-(4′-chlorophenoxy)phenyl methyl sulfide, 4.

Step 3

Into a separate reactor was charged 4-(4′-chlorophenoxy)phenyl methylsulfide, 4, and CH₂Cl₂ (26 Kg). The resultant solution was cooled toless than 10° C. and then treated with SO₂Cl₂ at such a rate so that thetemperature did not exceed 10° C. (30 min. required for the addition).An additional 2 Kg of CH₂Cl₂ was used to rinse in the SO₂Cl₂. Afterstirring for 1 h, the mixture was warmed to room temperature (degassingoccurs) and then further warmed to reflux for 30 minutes. Upon coolingto room temperature, the product solution was washed with water (15.5Kg) and then with brine (10.3 Kg). The stirred organic solution was thentreated with a slurry of MgSO₄ (2.6 kg) in CH₂Cl₂ (5 kg). The drying wasallowed to proceed overnight and the mixture was filtered to remove thedrying agent. The solids were washed with CH₂Cl₂ (20.7 kg) and thecombined organics were concentrated to effect azeotropic drying (38 kgof distillate collected, Karl Fischer shows 0.026% water inconcentrate). The product was treated with CH₂Cl₂ (19.8 kg) and then wasreconcentrated (19.8 kg distillate, Karl Fischer now at 0.014%). HPLCanalysis showed 94.7% 4-(4′-chlorophenoxy)phenyl chloromethyl sulfide,5.

B. Preparation of Silylketene acetal

Steps 4 and 5

Tetrahydropyran-4-carboxylic acid ethyl ester, 9, was prepared fromcommercially available diethylmalonate via steps 4 and 5 using knownliterature procedures as described in for example, U.S. Pat. Nos.5,412,120; 5,414,097; and EP584663 A2.

Step 6

To a nitrogen purged reactor was charged 26.8 kg (67.37 mole) of asolution of LDA. This was cooled to −15° C. and then a mixture of TMSCl(7.32 kg, 67.37 mole) and tetrahydropyran-4-carboxylic acid ethyl ester,9, (10.32 kg, 65.3 mole) was added at such a rate that the temperaturedid not exceed −10° C. (1 h addition time). An additional 0.2 kg ofTMSCl was added in one portion. The resultant mixture was heated to 20°C. and, after 4 h, a vacuum of 28 mm Hg was applied. The mixture washeated to 65° C. to remove volatiles. Toluene (11.95 kg) was added andthe distillation continued. When no more distillate collected, themixture was cooled to 25° C. A slurry of celite (2.7 kg) in hexane (20.6kg) was added. After stirring 1 h, the mixture was filtered through aprecoated Nutsche filter (1.5 kg of celite in 5 kg of hexane forprecoat). The reactor was rinsed with hexane (11 kg), and this was usedto rinse the filter. The combined organics were concentrated to an oilusing 19-25 mm Hg and mild heating. The concentrate was transferred to anitrogen purged storage vessel with the aid of CH₂Cl₂ (7 kg) to give17.5 kg of a solution of silylketene acetal 10.

C. Preparation of4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-4-(N-hydroxycarboxamido)tetrahydropyran

Step 7

90% of the silylketene acetal solution from Step 6 was charged to thereactor containing 4-(4′-chlorophenoxy)phenyl chloromethyl sulfide 5,followed directly by a slurry of ZnCl₂ (0.59 kg, 4.34 mole) in CH₂Cl₂ (5kg). The red reaction mixture was heated to reflux for 14 h (minimalheating required during first 1 h due to exotherm), at which point HPLCshowed about 10% starting material. The remaining 10% of the keteneacetal was added and the mixture was heated at reflux with collection ofthe CH₂Cl₂ to a pot temperature of 68° C. HPLC analysis of an aliquotshowed <1% starting material. Ethanol (15.5 kg), water (20.6 kg), and45% KOH (20.3 kg) were added to the concentrated product mixture. Thetwo phase mixture was stirred at 65° C. overnight (17 h) and was thenwarmed to a pot temperature of 90° C. to complete the saponification andto distill the ethanol. The mixture was cooled to 60-65° C. and hexane(41 kg) was added. After stirring 10 min. and then allowing layerseparation, the lower layer was transferred to another reactorcontaining water (24 kg) and 37% HCl (21.6 kg). Simultaneous with thistransfer, EtOAc (134.5 kg) was pumped to the receiving reactor. Thehexane solution was washed once with 65° C. water (25 liters) which wasthen transferred to the receiving reactor. This reactor now contained anEtOAc solution of the product acid and a lower aqueous layer. The lowerlayer was separated and replaced with 50 L of 65° C. water. Afterstirring briefly, the layers were separated. The organic solution wasconcentrated as much as possible using partial vacuum. CH₃CN (93.5 kg)was added and distillation continued at atmospheric pressure to a finalvolume of 90 liters. The mixture was cooled over 8 h to 5° C. and washeld there 8 h. The solids were collected on a filter and were washedwith CH₃CN (15 kg) and hexane (15.5 kg). After drying at 78° C. and 24mm Hg to constant mass, there was obtained 16.34 kg of the product acid,12, as a dense, slightly off-white solid. HPLC purity was 99%.

Step 8

A clean, dry 100 gallon reactor was charged with4-carboxy-4-{4-(4-chlorophenoxyphenyl)thiomethyl}tetrahydropyran 12(15.45 kg, 40.7 moles). To this reactor was added dichloromethane (77.2L, 102 kg). The suspended carboxylic acid was chilled to 0-5° C. underN₂ with agitation. A catalytic amount of N,N-dimethylformamide (0.1 l)was charged, followed by slow addition of oxalyl chloride (5.3 kg, 3.6L). The contents of the reactor were agitated and the internaltemperature was allowed to rise to ambient over a 4-12 hour period toallow conversion to the acid chloride. Another clean, dry 100 gallonreactor was charged with tert-butanol (26.8 kg, 34.5 L), tetrahydrofuran(75.4 kg, 84 L) and hydroxylamine (50 aqueous, 17 kg, 15.8 L). Thecontents of this reactor were agitated at ambient temperature. Thecontents of the reactor containing the acid chloride were chilled to0-5° C. Slow addition of the hydroxylamine solution is begun. The rateof addition was regulated such that the internal temperature of the acidchloride solution does not rise above 10° C. When the addition iscomplete, the contents of the reactor containing the newly formedhydroxamic acid were warmed to 20-25°. After a check for reactioncompleteness (HPLC or TLC), the solvent was removed in vacuo keeping thecontents of this reactor below 45° C. When little solvent is left todistill, the reactor was charged with acetonitrile (48.6 kg, 61.7 L).The contents were heated to reflux, and water (61.7 L) was added over aperiod of 30-50 minutes. The contents of the reactor were cooled to 0-5°C. over a period of 2-4 hours and slowly agitated for 4-14 hours. Thesolid hydroxamic acid 13, was collected by filtration and washed withwater. Typically, the wetcake so obtained is not dried but used as is.However, drying can be accomplished in vacuo at ca 50° C. The solid(21.5 kg wet, 14.45 kg dry, 90.1%) was 99.8% pure by area normalizationHPLC.

Step 9

A clean, dry 100-gallon reactor was charged with oxone® (potassiumperoxymonosulfate, 37.07 kg, 60.3 moles). Deionized water was added(88.3 kg) and the contents of the reactor were agitated and heated (toca. 35-40° C.) to dissolve the oxone. Another clean, dry 100 gallonreactor was charged with the hydroxamic acid, 13, (21.18 kg waterdampcake, 14.45 dry weight, 36.7 moles) and dissolved inN-methyl-2-pyrrolidinone (100.5 kg) with agitation. The contents of thisreactor were heated to 30-35° C. The aqueous oxone™ solution was addedto the reactor containing the hydroxamic acid at such a rate that theinternal temperature did not exceed 49° C. After the addition of oxone™was complete, the mixture was assayed by HPLC and TLC. When the reactionwas complete, typically in 0 to 1 hour post addition (HPLC data areanormalization purity is typically >98.5% desired product) the productwas treated with deionized water (25 kg) and cooled to 20° C.Crystallization of the crude product typically occurred at 20-25° C.(22° C. in this example). The mixture was then cooled to 5° C. andstirred for 10-14 hours (12 in this example). The precipitated productwas collected by filtration and washed well with deionized waterfollowed by hexanes. This wet cake (47.9 kg) was charged into a clean,dry, residue free 100-gallon reactor. Ethyl acetate (140 kg) was chargedto the solid followed by deionized water (120.6 kg). The contents of thereactor were agitated and heated (to ca 60° C.). Agitation was stoppedand the layers were allowed to separate. The aqueous layer wasseparated. Optionally, this can be followed by an aqueous NaHCO₃ washand water wash. The organic layer was filtered through a 5-10μ cottonfilter into a clean, dry, residue free reactor. The mixture wasconcentrated in vacuo to approximately 50% (ca 50 L) of the startingvolume. The solid was separated and recrystallized from ethyl acetateafter heating to approximately 70° C. and cooling to 5° C. The solid wascollected by filtration in a clean dry filter and dried at 40-45° C.under a nitrogen stream (an agitated filter was used for this example).11.82 kg of final product,4-[4-(4-chlorophenoxy)phenylsulfonylmethyl]-4-(N-hydroxycarboxamido)tetrahydropyran,compound 14, was obtained in 75.6% yield (99.8% pure by areanormalization HPLC) upon vacuum drying.

The foregoing invention has been described in some detail by way ofillustration and example, for the purposes of clarity and understanding.It will be obvious to one of ordinary skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined with reference to the followingappended claims, along with the full scope of equivalents to which suchclaims are entitled.

The patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

What is claimed is:
 1. A compound ZCH₂S—Ar¹—A—Ar², wherein: Ar¹ and Ar²are independently optionally substituted phenyl; Z is halo; and A isoxygen or CH₂.
 2. The compound of claim 1, wherein: Ar¹ is phenyl; Ar²is halophenyl; and A is oxygen.
 3. The compound of claim 2 wherein Ar²is chlorophenyl, and Z is chloro, i.e., 4-(4-chlorophenoxy)phenylchloromethyl sulfide.
 4. The compound which is 4-(4-chlorophenoxy)phenylmethyl sulfide.